Merkel cell polyomavirus small T antigen activates noncanonical NF-kB signaling to promote tumorigenesis

Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence-associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NF-kB (ncNF-kB), instead of canonical NF-kB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-kB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-kB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT-expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-kB pathway activation and SASP gene expression, and the inhibition of ncNF-kB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT-induced ncNF-kB signaling as an essential tumorigenic pathway in MCC. Implications: This work is the first to identify the activation of ncNF-kB signaling by any polyomavirus and its critical role in MCC tumorigenesis.